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Gene Therapy: Technical, Regulatory and Stakeholder issues Shefaly Yogendra Doctoral Scholar, University of Cambridge, UK TMP GRADUATE CONSORTIUM MIT, CAMBRIDGE, USA © PARLIAMENTARY COPYRIGHT 2005 Background Status and role of the Parliamentary Office of Science and Technology (POST) Target audience mainly non-science and non-technical MPs and peers POSTnote™ and longer reports POST Fellowships www.parliament.uk/post © PARLIAMENTARY COPYRIGHT 2005 POSTnote – Gene Therapy 2003: UK government pledges £50M over 3 years to harness potential of genetic technologies (£10M for gene therapy) Late 2003: China approves ‘Gendicine’, a gene therapy for head and neck cancer 2005: First marketing authorisation application for a gene therapy for a type of brain cancer by a UK firm expected © PARLIAMENTARY COPYRIGHT 2005 What is gene therapy? Introduction of genetic material into a cell to treat disease Various ways: Supply functioning copies of a malfunctioning gene Switch specific genes on or off Introduce genetic material to kill cancer cells or suppress tumours Stimulate immune system to attack certain types of ‘invaders’ Still in clinical trial stage in most cases, regulated as a research protocol © PARLIAMENTARY COPYRIGHT 2005 Administering gene therapy Two ways: Insert therapeutic material into cells from affected tissue outside body and return them to the body Deliver therapeutic material directly to the affected tissue or organ Either way, a ‘vector’ is used Most vectors are modified viruses, due to their efficiency in targeting and entering cells Over 70% of UK trials involve viral vectors © PARLIAMENTARY COPYRIGHT 2005 Success in gene therapy requires… Genetic malfunction is understood Therapeutic material can be delivered to target cells in affected tissue/ organ Therapeutic material is active for intended duration and delivers intended benefit Harmful side effects, if any, are manageable © PARLIAMENTARY COPYRIGHT 2005 UK regulation of gene therapy Advice of Clothier Committee 1992 Gene Therapy Advisory Committee (GTAC) Medicines and Healthcare Products Regulatory Agency (MHRA) Assess ethical acceptability of proposals taking into account scientific merit, benefits and risks Ministerial advice, regulatory ‘networking’ and foresight License clinical trials in the UK Competent to regulate medicinal products and devices UK Clinical Trials Regulation 2004 prohibits germ line gene therapy for ethical and safety reasons © PARLIAMENTARY COPYRIGHT 2005 UK gene therapy clinical trials Since 1993, 96 trials approved 72% cancer 13% for single-gene disorders 7% for vascular diseases Majority very small Phase I trials (with as few as 16-18 patients sometimes) In UK, only 3 Phase III trials – one in HIV and two in a type of brain cancer © PARLIAMENTARY COPYRIGHT 2005 Technical issues Gene delivery Not easy or predictable e.g. contrast between CF and X-SCID Durability and integration Where long-term effect desirable, therapeutic material must remain active for the duration Achieved through multiple rounds of therapy or through integrating therapeutic material Raises concerns about undesirable side effects, e.g. X-SCID Ongoing search for stable, non-integrating vectors © PARLIAMENTARY COPYRIGHT 2005 Technical issues Durability and integration Where more immediate effect required, integration is not an aim e.g. in cancer Immune response Body responds to viral vector as invader In some cases, such as cancer, triggering such immune response is the aim of the therapy In most cases, immune response may reduce efficacy of gene therapy by reducing patient responsiveness and increasing resistance to multiple rounds of therapy © PARLIAMENTARY COPYRIGHT 2005 Technical issues Safety of vectors Only 2 fatalities directly attributable to gene therapy, yet concerns raised Animal research may provide vital information about vector safety Uncertainty Complexity of process makes undesirable outcomes difficult to explain Uncertainty inherent to the process © PARLIAMENTARY COPYRIGHT 2005 Regulatory challenges Paediatric research Ethical issues No European guidelines yet Informed consent hard to obtain Accountability, openness and transparency Case-by-case approach but GTAC/ MHRA criticised for ‘closed door’ approach Public database in UK for NHS-sponsored clinical trials as well as recently announced voluntary measures by industry welcome steps © PARLIAMENTARY COPYRIGHT 2005 Regulatory challenges Resources Growing research investment More work likely for GTAC/ MHRA Future challenges New technologies emerge e.g. RNAi, presently reviewed case-by-case Blurred boundaries of science © PARLIAMENTARY COPYRIGHT 2005 Stakeholder issues: insights This slide under Chatham House Rule Department of Health Regulators Research community Patient interest groups Industry © PARLIAMENTARY COPYRIGHT 2005 Future prospects Much funding directed at disease-led research Satisfactory for patient interest groups Researchers demand more basic research into vector safety, delivery techniques and uncertainty of outcomes Varied expectations of a commercial gene therapy product in the UK market Patient interest groups realistic about a 10-15 year horizon Complications arising from European centralised approval process for biologics © PARLIAMENTARY COPYRIGHT 2005